This invention pertains to the controlled delivery of pharmaceutical agents and dosage forms therefor. In particular, the invention is directed to improved methods, dosage forms and devices for the controlled delivery of liquid active agent formulations to an environment of use.
Administration of liquid, active agent formulations is often preferred over solid active agent formulations in order to facilitate absorption of the active agent and obtain a beneficial effect for the intended use in the shortest possible time after the formulation is exposed to the environment of use. Examples of prior art devices to deliver liquid, active agent formulations are soft gelatin capsules that contain a liquid active agent formulation or liquid formulations of the active agent that are bottled and dispensed in measured dosage amounts by the spoonful, or the like. Those systems are not generally amenable to controlled delivery of the active agent over time. While it is desired to have the active agent exhibit its effect as soon as it is released to the environment of use, it also often is desirable to have controlled release of the active agent to the environment of use over time. Such controlled release may be sustained delivery over time, such as zero order, or patterned delivery, such as pulsatile for example. Prior art systems have not generally been suitable for such delivery.
Various devices and methods have been described for the continuous delivery of active agents over time. Typically, such prior art systems have been used to deliver active agents initially in the dry state prior to administration. For example, U.S. Pat. Nos. 4,892,778 and 4,940,465, which are incorporated herein by reference, describe dispensers for delivering a beneficial agent to an environment of use that include a semipermeable wall defining a compartment containing a layer of expandable material that pushes a drug layer out of the compartment formed by the wall. The exit orifice in the device is substantially the same diameter as the inner diameter of the compartment formed by the wall.
U.S. Pat. No. 4,915,949, which is incorporated herein by reference, describes a dispenser for delivering a beneficial agent to an environment of use that includes a semipermeable wall containing a layer of expandable material that pushes a drug layer out of the compartment formed by the wall. The drug layer contains discrete tiny pills dispersed in a carrier. The exit orifice in the device is substantially the same diameter as the inner diameter of the compartment formed by the wall.
U.S. Pat. No. 5,126,142, which is incorporated herein by reference, describes a device for delivering an ionophore to livestock that includes a semipermeable housing in which a composition containing the ionophore and a carrier and an expandable hydrophilic layer is located, along with an additional element that imparts sufficient density to the device to retain it in the rumen-reticular sac of a ruminant animal. The ionophore and carrier are present in a dry state during storage and the composition changes to a dispensable, fluid-like state when it is in contact with the fluid environment of use. A number of different exit arrangements are described, including a plurality of holes in the end of the device and a single exit of varying diameter to control the amount of drug released per unit time due to diffusion and osmotic pumping.
It is often preferable that a large orifice, from about 50%-100% of the inner diameter of the drug compartment, be provided in the dispensing device containing the active agent and a bioerodible or degradable active agent carrier. When exposed to the environment of use, drug is released from the drug layer by erosion and diffusion. In those cases where the drug is present in the solid state, the realization of the beneficial effect is delayed until the drug is dissolved in the fluids of the environment of use and absorbed by the tissues or mucosal environment of the gastrointestinal tract. Such delay often is not tolerable. Also, for drugs that are poorly soluble in gastric or intestinal fluids, the delay may be further exacerbated.
Devices in which the drug composition initially is dry but in the environment of use is delivered as a slurry, suspension or solution from a small exit orifice by the action of an expandable layer are described in U.S. Pat. Nos. 5,660,861, 5,633,011; 5,190,765; 5,252,338; 5,620,705; 4,931,285; 5,006,346; 5,024,842; and 5,160,743. Typical devices include an expandable push layer and a drug layer surrounded by a semipermeable membrane.
When the active agent is insoluble or poorly soluble, prior art systems may not provide rapid delivery of active agent or concentration gradients at the site of absorption that facilitate absorption through the gastrointestinal tract. Various approaches have been put forth to address such problems, including the use of water-soluble salts, self-emulsifying compositions, polymorphic forms, powdered solutions, molecular complexes, micronization, eutectics, and solid solutions. An example of the use of a powdered solution is described by Sheth, et al., in xe2x80x9cUse of Powdered Solutions to Improve the Dissolution Rate of Polythiazide Tablets,xe2x80x9d Drug Development and Industrial Pharmacy, 16(5), 769-777 (1990). References to certain of the other approaches are cited therein. Additional examples of powdered solutions are described in U.S. Pat. No. 5,800,834. The patent describes methodology for calculating the amount of liquid that may be optimally sorbed into materials to prevent the drug solution from being exuded from the granular composition during compression.
U.S. Pat. No. 5,486,365, which is incorporated herein by reference, describes a spheronized material formed from a scale-like calcium hydrogen phosphate particulate material having a high specific surface area, good compressibility and low friability. That patent indicates that the material has the characteristic of high liquid absorption. However, the patent does not suggest that the material may be used as a carrier for delivery of a liquid medicament formulation to the environment of use. Instead, the patent describes the formation of a dried formulation, such as formed by spray drying. The patent describes the use of a suspension containing medicines and binders during the spray-drying granulation process to form a spherical particle containing the medicine. As an example, ascorbic acid in an amount equivalent to 10% of the scale-like calcium hydrogen phosphate was dissolved into a slurry of 20 weight percent of calcium hydrogen phosphate in water, and the resulting slurry was spray dried to form dried, spherical calcium hydrogen phosphate containing ascorbic acid. That material was then tableted under loads of 500-2000 kg/cm2.
It has been surprisingly discovered that certain absorbent materials having prescribed physical characteristics, as exemplified by, for example, particular porous calcium hydrogen phosphate powders described in U.S. Pat. No. 5,486,365, sold under the trademark FujiCalin(copyright), and magnesium aluminometasilicate powders, sold under the trademark Neusilin(trademark) (Fuji Chemical Industries (U.S.A.) Inc., Robbinsville, N.J.), may be used to prepare dosage forms in which liquid, active agent formulations may be sorbed into the interior pores of the aforementioned materials in significant amounts and delivered to the site of administration in the liquid state. It has further been surprisingly discovered that such types of porous particles with liquid, active agent formulations sorbed into the particles may be fabricated into controlled release dosage forms without exuding the liquid, active agent formulation out of the particles during the manufacturing process. That discovery has permitted the fabrication of controlled release dosage forms that provided for the delivery of the active agent to the delivery site in the liquid state, thus providing minimal delay in the onset of the desired beneficial effect of the active agent, since the active agent does not have to be initially dissolved or dispersed in the form of microparticles at the site of action. Furthermore, such dosage forms may permit large concentration gradients of active agent in solution, and optional delivery of absorption enhancers, at the absorption site to facilitate absorption of the active agent. Microcrystalline cellulose, porous sodium carboxymethyl cellulose crosslinked sold as Ac-Di-Sol (FMC Corporation), porous soy bean hull fiber sold as Fl-1 Soy Fiber (Fibred Group), and silicon dioxide having high surface area and good absorption properties may also be used in the dosage forms described herein. However, the calcium hydrogen phosphate and magnesium aluminometasilicate particles as described herein are presently preferred.
Accordingly, in one aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation. Optionally, a flow-promoting layer may be interposed between the inner surface of the wall and at least the external surface of the drug layer located within the cavity. Also, a placebo layer to delay onset of delivery of the active agent optionally may be placed between the drug layer and the exit orifice.
In another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles, having a mean particle size of 50-150 microns, being formed by spray drying a scale-like calcium hydrogen phosphate with a specific surface area of 20 m2/g to 60 m2/g, an apparent specific volume of 1.5 ml/g or more, an oil absorption capacity of 0.7 ml/g or more, a primary particle size of 0.1xcexc to 5xcexc, and an average particle size of 2xcexc to 10xcexc among secondary particles that are aggregates of the primary particles, the scale-like calcium hydrogen phosphate being represented by the following general formula:
CaHPO4.mH2O 
wherein m satisfies the relationship 0xe2x89xa6mxe2x89xa62.0.
In yet another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being calcium hydrogen phosphate having a specific volume of at least 1.5 ml/g, a BET specific surface area of at least 20 m2/g, and a water absorption capacity of at least 0.7 ml/g. Preferably, the particles have a bulk density of 0.4-0.6 g/ml, a BET surface area of 30-50 m2/g, a specific volume of greater than 2 ml/g, and a mean pore size of at least 50 Angstroms.
In another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being calcium hydrogen phosphate having a specific volume of at least 1.5 ml/g, a BET specific area of at least 20 m2/g, and a water absorption capacity of at least 0.7 ml/g, the particles having a size distribution of 100% less than 40 mesh, 50%-100% less than 100 mesh and 10%-60% less than 200 mesh. Preferably, 100% is less than 40 mesh, 60%-90% is less than 100 mesh and 20%-60% is less than 200 mesh.
In yet another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being calcium hydrogen phosphate having a bulk specific volume of 1.5 ml/g-5 ml/g, a BET specific area of 20 m2/g-60 m2/g, a water absorption capacity of at least 0.7 ml/g, and a mean particle size of at least 70 micrometers.
In still another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally comprising a placebo (inert) layer between the exit orifice and the drug layer. Optionally, a flow-promoting layer may be interposed between the inner surface of the wall and at least the external surface of the drug layer located within the cavity.
In yet another aspect, the invention comprises a method of facilitating the release of an active agent from a dosage form comprising sorbing a liquid formulation of the active agent into a plurality of porous particles, the particles, having a mean particle size of 50-150 microns, being formed by spray drying a scale-like calcium hydrogen phosphate with a specific surface area of 20 m2/g to 60 m2/g, an apparent specific volume of
1.5 ml/g or more, an oil absorption capacity of 0.7 ml/g or more, a primary particle size of 0.1xcexc to 5xcexc, and an average particle size of 2xcexc to 10xcexc among secondary particles that are aggregates of the primary particles, the scale-like calcium hydrogen phosphate being represented by the following general formula:
CaHPO4.mH2O 
wherein m satisfies the relationship 0xe2x89xa6mxe2x89xa62.0, and dispersing the particles throughout a bioerodible carrier.
In another aspect, the invention comprises a composition comprising a liquid formulation of the active agent sorbed into a plurality of porous particles, the particles, having a mean particle size of 50-150 microns, being formed by spray drying a scale-like calcium hydrogen phosphate with a specific surface area of 20 m2/g to 60 m2/g, an apparent specific volume of 1.5 ml/g or more, an oil absorption capacity of 0.7 ml/g or more, a primary particle size of 0.1xcexc to 5xcexc, and an average particle size of 2xcexc to 10xcexc among secondary particles that are aggregates of the primary particles, the scale-like calcium hydrogen phosphate being represented by the following general formula:
CaHPO4.mH2O 
wherein m satisfies the relationship 0xe2x89xa6mxe2x89xa62.0, and dispersed throughout a bioerodible carrier, the particles being released in the environment of use over a prolonged period of time.
In yet another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being magnesium aluminometasilicate.
In still another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being magnesium aluminometasilicate represented by the general formula
Al2O3MgO.2SiO2.nH2O 
wherein n satisfies the relationship 0xe2x89xa6nxe2x89xa610.
In another aspect, the invention comprises a dosage form for an active agent comprising a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being magnesium aluminometasilicate represented by the general formula
Al2O3MgO.2SiO2.nH2O 
wherein n satisfies the relationship 0xe2x89xa6nxe2x89xa610 and having a specific surface area of about 100-300 m2/g, an oil absorption capacity of about 1.3-3.4 ml/g, a mean particle size of about 1-2 microns, an angle of repose about 25xc2x0-45xc2x0, a specific gravity of about 2 g/ml and a specific volume of about 2.1-12 ml/g.
The dosage forms of the invention may be fabricated with inert spacers between one or more drug layers to provide for pulsatile drug delivery or with a plurality of drug layers, each having a different active agent. Different active agents may be included within a single drug layer.
Generally, 5% and up to 70%, more often 20-70%, preferably 30-60%, and more preferably 40-60%, by weight of the liquid, active agent formulation may be loaded into the porous particles. Up to about 50% by weight of liquid active agent formulation may be loaded into the porous crystalline materials, such as calcium hydrogen phosphate particles, but more typically 30-40 weight percent. Higher loading is possible with amorphous porous carriers such as magnesium aluminometasilicates, which may contain up to 60-70% liquid, active agent formulation, more usually up to 60%. A small amount of a binder, e.g. up to 5-10% by weight, may be added to form the active agent layer with calcium hydrogen phosphate particles, as well as a tableting lubricant. For amorphous materials, usually less or no binder and lubricant are used. Blends of the various absorptive materials described herein may be used, such as for example, blends of crystalline material such as calcium hydrogen phosphate with the amorphous material such as magnesium aluminosilicate.